1. Field of the Invention
The present invention concerns vaginal delivery of chemotherapeutic agents and/or inhibitors of membrane efflux systems for cancer therapy and a method for treatment of cancer. In particular, the invention concerns a method, composition and device for a mucosal and transmucosal delivery of a chemotherapeutic agent and/or inhibitor of membrane efflux systems to the vagina for topical vaginal and/or systemic cancer therapy using a mucoadhesive composition directly or incorporated into an intravaginal medicated device.
The composition of the invention or intravaginal device medicated with the mucosal composition of the invention delivers the chemotherapeutic agent and/or inhibitor of membrane efflux system into the vagina, provides a continuous contact with the vaginal mucosa, releases the agent from the formulation and delivers it transmucosally into the systemic circulation. The composition permits delivery of the therapeutic agent transmucosally through a vaginal wall to the systemic circulation or topically to the vaginal mucosa. The method avoids intravenous administration, permits extended continuous or pulsed delivery of the chemotherapeutic agents and/or inhibitors of membrane efflux systems and achieves delivery of higher concentrations of such agents to a site of neoplasias in the female.
The mucoadhesive composition comprises at least a therapeutic agent, a mucoadhesive agent, a sorption promoter and a carrier and optionally a penetration enhancer.
The mucoadhesive composition or medicated intravaginal device of the invention permits administration of lower concentrations of the drug than those needed for systemic administration, prevents leaking of the drug out of the vagina, results in greater systemic bioavailability than after oral administration and enhances transmucosal absorption of chemotherapeutic agents.
2. Background and Related Disclosures
Treatment of cancer or a cellular malignancy where there is a loss of normal control over cell growth, which results in unregulated growth, lack of differentiation and ability to invade local tissues and metastasize, poses a great challenge for the whole medical community. Because of the cancer's great aggressiveness, the available treatments, such as radiation and chemotherapy utilizing cytotoxic agents, are typically also very aggressive. As a result, the treatments of cancer result in many adverse reactions and toxicity.
Successful cancer therapy must be diverted to the primary tumors and to metastases, typically requiring a systemic, mainly intravenous, drug administration. Because of their aggressivity and toxicity, such intravenous administration often leads to phlebitis or collapse of the veins. Moreover, for intravenous injections it requires delivery of the treatment in the hospital or doctor's office as well as periods of following observation. To date, alternative treatments which would enable home administration of these drugs are limited.
Thus, it would be advantageous to have available alternative routes of administration of the chemotherapeutic agents and/or inhibitors of membrane efflux systems which would permit self-administration or, through extension, on-going monitoring.
It has been estimated that in the United States half of the one million new cancer cases annually will be treated with systemic chemotherapy. Although the oral route would be the most preferred from a patient's perspective, absorption from the gastrointestinal tract is generally low due to various protein systems expressed in the intestinal mucosa. This includes metabolically active enzymes, such as cytochrome P450 superfamily, that degrade the therapeutic agent before it can reach the systemic distribution system. In addition, the intestinal mucosa contains a high level of specialized transport proteins that remove structurally unrelated drug molecules before reaching the systemic circulation. Examples of such membrane efflux systems that belong to the ABC transporter superfamily are P-glycoprotein (P-gp) and multidrug-resistance associated protein (MRP). It is also known that drug metabolizing enzymes and membrane efflux systems in the gastrointestinal mucosa act in concert, which results in low oral bioavailability of drugs that are substrates for both systems.
Biochemically, efflux systems in the gastrointestinal tract are related to the proteins that cause failure of chemotherapy in cancer patients as a result of multidrug resistance (MDR), as described in Ann. Rev. Cell Biol., 8:67 (1992). It is well documented that overexpression of membrane efflux systems such as P-gp and MRP in tumor cells confer MDR by actively decreasing net intracellular accumulation of diverse cytotoxic drugs (J. Biol. Chem., 263:12163 (1998); PNAS (USA), 85:3680 (1988); Semin. Cancer Biol., 2:213 (1991); and J. Biol. Chem., 270:16167 (1995)).
A new treatment of drug-resistant tumor cells includes administration of inhibitors of membrane efflux systems. The treatment with these inhibitors significantly increase accumulation of chemotherapeutic agents in drug-resistant tumor cells and, hence, provide a more effective tumor therapy at lower doses of the chemotherapeutic agents. However, since P-gp and MRP are also expressed in the gastrointestinal mucosa, where they serve as an important physiological defense barrier to environmental toxins, oral administration of inhibitors of membrane efflux systems may have only limited efficacy and also cause severe toxic side effects. As a consequence, administration of inhibitors of membrane efflux systems in cancer therapy is currently limited to the parenteral route using injections or short-term infusions.
Thus, it would be advantageous to have available alternative treatment which would overcome these intestinal membrane efflux systems and provide a continuous and predictable delivery of the chemotherapeutic drugs and/or inhibitors of membrane efflux systems to the tumor. To lessen toxicity of these drugs, such delivery should be preferably via absorption through other mucosal tissues than alimentary tract and should deliver the drug transmucosally to the general blood circulation to avoid a necessity to administer the drug intravenously.
Transvaginal delivery systems according to the invention could thus offer an alternative effective means of delivering therapeutic quantities of chemotherapeutic drugs for the treatment of neoplastic growth in the female because, in contrast to the gastrointestinal mucosa, the expression level of membrane efflux systems in the vaginal mucosa is significantly reduced.
Transvaginal delivery of anti-inflammatory and other drugs via a vaginal device has been discovered by inventors and is disclosed in the U.S. Pat. Nos. 6,086,909, 6,197,327 and 6,416,779 B1, incorporated herein by reference.
It is therefore a primary objective of this invention to provide a device, composition and a method for administration of chemotherapeutic agents and/or inhibitors of membrane efflux systems by transmucosal or topical vaginal delivery. The method of the invention provides a novel route of delivery of chemotherapeutic agents for treatment, control or maintenance of cancer which eliminates the need for parenteral administration, permits extended continuous or pulsed delivery of the drug to the vaginal mucosa locally and topically and transvaginal delivery of the drug to the general circulation. Additionally, the vaginal delivery of inhibitors of membrane efflux systems reduces the risk of toxic side effects following administration to cancer patients diagnosed with drug-resistant tumors. The method for treatment, control and maintenance of cancer comprises administering the chemotherapeutic agents and inhibitors of membrane efflux system intravaginally to the mucosa or transmucosally to the systemic circulation.
All references, patents and patent applications cited herein are hereby incorporated by reference in their entirety.